Assembly for heat treatment of biological tissues

ABSTRACT

The invention concerns an assembly for heat treatment of a region of a biological tissue ( 410 ) comprising energy-generating means ( 100 ) to supply energy to the region; means ( 200 ) for measuring and recording spatial temperature distribution in said region; a control unit ( 300 ) comprising means for point-to-point digital processing of the temperature distribution in the region. The invention is characterised in that the energy-generating means comprise means( 110 ) for spatial and temporal distribution of the power available to them on said region, the control unit ( 300 ) comprising means ( 330, 350 ), based on the temperature distribution, for controlling the amount and distribution of energy supplied by the generating means ( 100 ).

[0001] The invention relates to local hyperthermia therapies.

[0002] Local hyperthermia therapies are techniques that are commonlyused to locally treat biological tissues. They consist in heating atarget zone of the biological tissue using an energy source (laser,microwave, radiofrequency wave, ultrasound, etc.).

[0003] These techniques offer numerous advantages. From the qualitativeviewpoint, they offer a great deal of potential for controllingtreatments such as gene therapy, the localized application of drugs, theablation of tumours, etc. From an economic viewpoint, they arecompatible with ambulatory treatment of the sick and therefore make itpossible to reduce the hospitalization time.

[0004] In general, local hyperthermia therapies allow medicalinterventions the invasive nature of which is reduced to a minimum.

[0005] Among the types of energy used, focused ultrasound (FUS) isparticularly advantageous because it is able to heat the focused-onzone, in a non-invasive way, deeply within the biological body, withoutsignificantly heating the tissues adjacent to the focused-on zone.

[0006] During treatment, the temperature of the target zone and of itsimmediate surroundings needs to be controlled precisely andcontinuously, although the supply of energy is localized and fast (ofthe order of a few seconds). Patent FR 2 798 296 filed on Sep. 13, 1999in the name of the Centre National de la Recherche Scientifique (CNRS)describes an assembly for the heat treatment of biological tissues. Theassembly described in that document takes account of the actual spatialdistribution of temperature in the target zone and in its immediatesurroundings. This spatial distribution makes it possible to estimateprecisely how much energy needs to be applied and to influence theenergy source accordingly. Such an assembly makes it possible bothquickly to obtain the desired temperature in the target zone and tomaintain and control the temperature in this target zone with increasedprecision, by comparison with that which was possible with earliertechniques.

[0007] The disadvantage with this assembly is that it is based on amodel of a heated region that is very localized in space. Inconsequence, it allows control over the change in temperature in thetarget zone but does not allow control over the temperature distributionwhen several energy sources are used or when the energy is appliedsimultaneously to several places, for example using an array ofemitters.

[0008] It is an object of the present invention to alleviate thesedisadvantages by proposing a heat treatment assembly that allowsextended control of the temperature in a region of the living tissue andthat can be applied without spatial limitation as regards theapplication of energy.

[0009] To this end, the invention proposes an assembly for the heattreatment of a region of biological tissue comprising:

[0010] energy-generating means to supply energy to the region,

[0011] means for measuring and recording the spatial temperaturedistribution in said region,

[0012] control unit comprising numerical processing means for thepoint-by-point processing of the spatial temperature distribution in theregion, characterized in that the energy-generating means comprise meansfor spatially and temporally distributing the power that they apply tothe aforesaid region, the control unit comprising means for, on thebasis of the temperature distribution, controlling the amount anddistribution of the energy supplied by the generating means.

[0013] The means for spatially and temporally distributing the powerapplied consist, for example, of an ultrasound transducer whose movementin space is controlled. The heated region can therefore be broader thanthe initial distribution of the energy source.

[0014] The heat treatment assembly according to the present inventionadvantageously takes account of the spatial temperature distribution ateach point in the region. Unlike the heat treatment assemblies of theprior art, this characteristic allows control over the distribution ofenergy throughout the treated region rather than simply of the energyapplied at a focused-on point. It thus allows three dimensional andreal-time control over the change in temperature in the treatedbiological tissue.

[0015] Advantageously, the control unit of the heat treatment assemblymay comprise means for estimating the energy losses in the region of thetissue on the basis of an estimate of the thermal conductivity and ofthe spatial temperature distribution in the region and its surroundings.This allows the temperature distribution in the heat treated tissues tobe changed more quickly toward a reference distribution.

[0016] In one embodiment of the invention, the control unit comprisesprocessing means to take account of the thermal conductivity at eachpoint in the region.

[0017] In particular, the control unit may comprise means for measuringthe temperature at each point of a plurality of points sampling theregion and at regular time intervals and to deduce therefrom an estimateof the change in temperature as a function of thermal conductivity fromone point of the spatial sample to another.

[0018] According to this implementation, the image of the region of thebiological tissue is broken down into voxels and each voxel isassociated with a point in the region. The processing unit associates athermal conductivity and a temperature with each point. This“point-by-point” breakdown advantageously allows the change intemperature to be controlled throughout the region of the biologicaltissue.

[0019] Advantageously, the energy-generating means may emit focusedultrasound. Focused ultrasound allows heat to be supplied to a localizedzone, non-invasively, even if this zone is situated deep within thehuman body or the animal.

[0020] Advantageously, the means for measuring and recording the spatialtemperature distribution comprise a Magnetic Resonance Imaging apparatus(MRI). MRI allows full and non-invasive mapping of the temperatures inthe zone being treated, with good spatial resolution (of the order of 1millimeter) and excellent precision (of the order of 1° C.).Furthermore, the data collected by MRI can easily be numericallyprocessed.

[0021] In one implementation of the invention, the amplitude pw of thepower to be supplied at a point {right arrow over (r)} at an instantt+Δt is calculated using a relationship of the type:${pw} = \frac{{{Tp}\left( {\overset{\rightarrow}{r},{t + {\Delta \quad t}}} \right)} - {{FT}^{- 1}\left( {T*\left( {\overset{\rightarrow}{k},t} \right)^{{- k^{2}}D\quad \Delta \quad t}} \right)}}{{FT}^{- 1}\left( {\alpha \frac{1 - ^{{- k^{2}}D\quad \Delta \quad t}}{{Dk}^{2}}S*\left( \overset{\rightarrow}{k} \right)} \right)}$

[0022] where Tp({right arrow over (r)},t+Δt) is the referencetemperature at that point at the moment t+Δt, FT⁻¹ is an inverse Fouriertransform, T*({right arrow over (k)},t) is the Fourier transform of thetemperature measured at the moment t, D is the heat diffusioncoefficient for the tissue, α is the energy absorption coefficient forthe tissue, S*({right arrow over (k)}) is the Fourier transform of thespatial distribution of the applied energy S({right arrow over (r)}).

[0023] In this way, at each moment, the energy to be applied isautomatically controlled by the processing means so as to force thetemperature to follow a predefined reference profile. Thischaracteristic makes it possible to ensure optimum safety for thepatient. In practice, what this amounts to is calculating the power pwto be applied between two successive temperature measurements obtainedby MRI.

[0024] Of course, the energy-generating means for inducing hyperthermiain the region of the tissues being treated comprise energy sources ofthe ultrasound, laser, microwave or radiofrequency type.

[0025] Other features and advantages will become further apparent fromthe description which follows, which is purely illustrative andnonlimiting and is to be read with reference to the attached figuresamong which:

[0026]FIG. 1 schematically depicts the heat treatment assembly accordingto the invention;

[0027]FIG. 2 depicts the change in temperature at the focal point of thetransducer as a function of time when the method is applied to anacrylamide gel (test sample);

[0028]FIG. 3 depicts the change in power of the focused ultrasound as afunction of time when the method is applied to an acrylamide gel;

[0029]FIG. 4 depicts a change in temperature at the focus point of thetransducer as a function of time when the method is applied to a freshmeat sample;

[0030]FIG. 5 depicts the change in power of the focused ultrasound as afunction of time when the method is applied to a fresh meat sample;

[0031]FIG. 6 represents the change in temperature at the focal point ofthe transducer as a function of time when the method is applied in vivoto the thigh of a rabbit;

[0032]FIG. 7 depicts the change in power of the focused ultrasound as afunction of time when the method is applied to the thigh of a rabbit;

[0033]FIG. 8 depicts the variation in the minimum difference between thesimulated temperature and the reference profile as a function of theerror on the diffusion and absorption parameters of the treated tissues,which error is calculated as the ratio$\frac{\left( {D/\alpha} \right)\quad {erroneous}}{\left( {D/\alpha} \right)\quad {optimum}}$

[0034]FIG. 9 depicts the variation in the standard deviation of thedifference between the simulated temperature and the reference profileas a function of the error on the diffusion and absorption parameters ofthe treated tissues, which error is calculated as the$\frac{\left( {D/\alpha} \right)\quad {erroneous}}{\left( {D/\alpha} \right)\quad {optimum}}.$

[0035] One of the embodiments of the invention is described hereinbelowin detail. By way of example, this embodiment of the inventioncorresponds to a local hyperthermia treatment assembly using focusedultrasound (FUS) controlled by magnetic resonance imaging (MRI).

[0036] As depicted in FIG. 1, such an assembly comprises:

[0037] ultrasound generating means 100,

[0038] anatomical and temperature mapping means 200,

[0039] a temperature control unit 300,

[0040] a sample holder 400 for the biological tissue 410 to be treated.

[0041] In the embodiment of the invention described here, theenergy-generating means 100 are made up of a transducer 110 able to bemoved by a hydraulic system, of a sinusoidal signal generator 120, of anamplifier 130 and of a converter 140 connecting the sinusoidal signalgenerator 120 to the control unit 300.

[0042] The transducer 110 has a diameter of 90 mm with a radius ofcurvature of 80 mm. The focal length can be adjusted electronicallybetween 50 and 125 mm and the position of the focal region can bealtered mechanically in the horizontal plane in a field of 80 mm×80 mm.It operates at 1.5 MHz. The input signal is generated by a multi-channelsquare wave generator. The signals are filtered so as to avoidinterference with the magnetic resonance instruments that operate, forexample, at 63 MHz for a 1.5T MRI apparatus.

[0043] The generator 120 is, for example, a multichannel generator(Corelec) driven by a serial connection. The system for moving thetransducer in a horizontal plane is, for example, a hydraulic systemdriven by a serial link.

[0044] The aforesaid two links are connected, for example, to the PCreceiving the MRI images in real time and producing temperature maps soas to allow the desired feedback control of temperature.

[0045] The mapping means 200 are able to measure and record the spatialtemperature distribution. They comprise, for example, an MRI apparatusof the ACS NT 1.5 T type marketed by Philips® (Best, Netherlands). Thecontrol unit 300 in particular comprises a work station 310 of the PCtype, marketed by Dell®. The PC is able to control the ultrasoundgenerator 100 and the system for moving the transducer 110. In thisdevice, all the parameters concerned with the application of energy byfocused ultrasound can therefore be adjusted through the work station:the power of the ultrasound, the focal length and the position of thetransducer 110. The work station further comprises a graphics interfaceso that the progress of the intervention can be viewed in real time.

[0046] The control unit 300 also comprises means for alleviating andnumerically processing the spatial temperature distribution 320, meansfor determining the value of the power 330 that needs to be supplied toa target zone of the controlled region, means 340 for estimating thermalenergy losses in the region considered and control means 350 forcontrolling the energy-generating means. The control means 350 tell theenergy-generating means 100 to deliver the amount of power determined bythe means for determining the power level 330.

[0047] The sample holder 400 comprises a support 420. This supportcontains the transducer 110 and a surface coil (MRI signal receiver).The support 420 is placed in a water-filled reservoir so as to ensureoptimum propagation of the focused ultrasound toward the target tissues.The water is kept at a constant temperature of 38° C. using a water bathtemperature controller (for example polysciences, model 9110-BB, IL,USA) to avoid the tested samples cooling.

[0048] The object of an automatic temperature control method is to forcethe temperature at a given position in the region of the samples fortreatment to follow a reference profile Tp(t). The change in temperaturein space and in time is given by the bio-heat equation [1] that takesaccount of the coefficient of energy absorption by the tissue (α) andthe coefficient of diffusion of heat into the tissue (D):$\begin{matrix}{\frac{\partial{T\left( {\overset{\rightarrow}{r},t} \right)}}{\partial t} = {{D \cdot {\nabla^{2}{T\left( {\overset{\rightarrow}{r},t} \right)}}} + {\alpha \quad {{S\left( \overset{\rightarrow}{r} \right)} \cdot {{pw}(t)}}}}} & \lbrack 1\rbrack\end{matrix}$

[0049] where T({right arrow over (r)},t) is the temperature map, ∇² isthe Laplace operator, S({right arrow over (r)}) is the spatialdistribution of the applied energy and pw(t) is its amplitude.

[0050] This equation does not take account of perfusion in the tissuesor of the heat produced by metabolism because the heat generated isneglible by comparison with the amount of heat applied by focusedultrasound (FUS). The invention generalizes the control principle basedon equation 1 with no constraint regarding the spatial distribution ofthe application of energy by taking account of the heat transfer fromeach point (or voxel) to each other point (or voxel). To do that, ananalytical solution for equation [1] is sought in order best to predictthe temporal change in temperature at any point in space as a functionof the diffusion and the application of energy by the source. TheFourier transform on the spatial coordinates of equation [1] leads to alinear equation of the first order as a function of time:$\begin{matrix}{\frac{{\partial T}*\left( {\overset{\rightarrow}{k},t} \right)}{\partial t} = {{{- k^{2}}{DT}*\left( {\overset{\rightarrow}{k},t} \right)} + {\alpha \quad S*{\left( \overset{\rightarrow}{k} \right) \cdot {{pw}(t)}}}}} & \lbrack 2\rbrack\end{matrix}$

[0051] where T*({right arrow over (k)},t) and S*({right arrow over (k)})are the Fourier transforms on the spatial coordinates of T({right arrowover (r)},t) and S({right arrow over (r)}) respectively.

[0052] A solution can be derived from equation [2] by assuming the powerpw(t) is constant for a given time interval Δt (corresponding to themeasurement interval for temperature measurements by MRI):$\begin{matrix}{{T*\left( {\overset{\rightarrow}{k},{t + {\Delta \quad t}}} \right)} = {{^{{- k^{2}}D\quad \Delta \quad t}T*\left( {\overset{\rightarrow}{k},t} \right)} + {\alpha \frac{1 - ^{{- k^{2}}D\quad \Delta \quad t}}{{Dk}^{2}}S*{\left( \overset{\rightarrow}{k} \right) \cdot {pw}}}}} & \lbrack 3\rbrack\end{matrix}$

[0053] In consequence, the power to be applied during At to force thetemperature T({right arrow over (r)}, t+Δt) to be equal to a temperatureprofile Tp({right arrow over (r)}, t+Δt) can be derived from the inverseFourier transform (FT⁻¹) of equation [3]: $\begin{matrix}{{pw} = \frac{{{Tp}\left( {\overset{\rightarrow}{r},{t + {\Delta \quad t}}} \right)} - {{FT}^{- 1}\left( {T*\left( {\overset{\rightarrow}{k},t} \right)^{{- k^{2}}D\quad \Delta \quad t}} \right)}}{{FT}^{- 1}\left( {\alpha \frac{1 - ^{{- k^{2}}D\quad \Delta \quad t}}{{Dk}^{2}}S*\left( \overset{\rightarrow}{k} \right)} \right)}} & \lbrack 4\rbrack\end{matrix}$

[0054] This type of algorithm makes it possible to ensure optimum safetyfor the patient because it makes it possible automatically to controlthe temperature. For this, the energy to be applied in order to forcethe temperature to follow a predefined reference profile is evaluated atregular time intervals Δt. In practice, what this amounts to iscalculating the power pw to be applied between two successivetemperature measurements obtained by MRI. Ideally, this type ofalgorithm takes the physical phenomenon (in this instance the heatdiffusion equation) into consideration and is as robust as possible.

Setting Up the Device

[0055] All the experiments were carried out according to the sameprotocol. The position of a reference volume was acquired in order todefine a region of interest and the position of the reference focalpoint. The position of the reference volume with respect to theisocenter of the magnet of the MRI apparatus was recorded so as toposition the transducer 110 and to adjust the focal length. Next, arepeated scan of this volume was done to prepare the heating process.This preparation was used to:

[0056] calculate the standard deviation at the temperature mean in eachvoxel of the volume so as to estimate the precision of the temperaturemeasurement,

[0057] correct the position of the transducer 110 and its focal length;low-power focused ultrasound was applied for a brief period (of theorder of 5s) so as to induce modest hyperthermia (about +3° C.). Thismeasurement made it possible to check the coordinates of the position ofthe image by magnetic resonance and the position of the transducer andthe focal length were adjusted if necessary,

[0058] evaluate the diffusion D and absorption a parameters of thetissue: focused ultrasound was applied for a brief period and anon-linear adjustment was made using the method of least squares to thecurve of the change of temperature at the focal point as a function oftime so as to obtain these parameters.

[0059] Following this preparatory protocol, the desired change intemperature as a function of time (reference profile Tp({right arrowover (r)},t)) was programmed and the automatic control process (equation4) was begun.

[0060] To allow this process to operate correctly, it was necessary tosynchronize the MRI acquisition and the PC driving the focusedultrasound. For that, the MRI imaging device generates a TTL (Time toLive) signal at the start of each scan. This signal was detected by abuilt-in interface which switched a relay connected to a parallel portof the PC. This switching was detected by a special-purpose routinewritten in C and the corresponding PC system times were recorded in ashared memory module used by the algorithm. The timings thus measuredwere taken into consideration in the temperature control algorithm.

Experimental Procedure

[0061] Experiments on phantom gels, fresh meat samples and, in vivo onrabbit thighs, were carried out on the 1.5 Tesla Philips ACS/NT systemequipped with the Philips prototype focused ultrasound generator forinducing local hyperthermia. Rabbits were anesthetized and positioned insuch a way that the thigh muscles were centered approximately on theultrasound beam. The values of the coefficients a and D from preliminarymeasurements are given in the table below: Acrylamide Rabbit thigh gelFresh meat (in vivo) D (mm² · s⁻¹) 0.17 0.36 0.10 α (° C. · s⁻¹ · %⁻¹)0.33 0.29 0.40

[0062] When the preparatory adjustment phase had been carried out (seeabove), the real-time temperature control protocol was performed.

[0063] In these experiments, a temporal resolution of 1.75 seconds for 3parallel slices was obtained, using a “segmented EPI” imaging techniquewith the following parameters: an echo time (TE) of 30 ms, a repeat time(TR) of 60 ms and 11 phase encoding steps per TR with a spatialresolution 1×1 mm, 3 mm slice thickness.

[0064]FIGS. 2, 4 and 6 represent the change in temperature at the focalpoint of the focused ultrasound transducer as a function of time,obtained respectively with acrylamide gel, with a sample of fresh meat,and with a rabbit thigh. The curve in continuous line represents thereference temperature profile Tp(t) and the symbols represent theexperimental temperature data at the focal point, measured bytemperature MRI. As can be seen in FIG. 6, the application of focusedultrasound was halted after 170 s. The temperature then decreased to itsinitial value, with no control, on account of the diffusion phenomenon.

[0065] The standard deviation of the difference between the measuredtemperature and the reference temperature remained relatively constant(0.75° C. on average) during the hyperthermia phase, indicating that theproposed method makes it possible to perform effective real-time controlon the change in temperature in vivo.

[0066]FIGS. 3, 5 and 7 represent the change in focused ultrasound poweras a function of time when the method is applied respectively to theacrylamide gel, to the fresh meat sample and to the rabbit thigh.

[0067] It is evident that the values of the coefficients a and D canvary during the experiment (as a function of temperature, because of thedenaturing of proteins, change in perfusion, etc.). It is thereforeimportant to make sure that the proposed temperature control algorithmis not excessively sensitive to a variation in these parameters.

[0068] The sensitivity of the quality of the temperature control wasestimated from numerical simulations, by varying the parameters D and αover a wide range of values between 30% and 230% and between 50% and150%, respectively, of their initially (on the basis of the preparatoryphase) estimated value, in steps of 2%. For each (α, D) pairing, thechange in temperature was calculated using the power actually appliedduring the experiment. The results obtained show that the temperaturefollows the temperature profile with an offset and with a fluctuationthat vary to greater or lesser extents. The minimum difference betweenthe simulated temperature and the reference temperature gives the offsetvalue and the standard deviation of this difference allows the amplitudeof the fluctuation to be evaluated.

[0069]FIG. 8 depicts the variation in the minimum difference between thesimulated temperature and the reference profile as a function of theerror on the diffusion and absorption parameters of the treated tissues,which error is calculated as the ratio$\frac{\left( {D/\alpha} \right)\quad {erroneous}}{\left( {D/\alpha} \right)\quad {optimum}}$

[0070]FIG. 9 depicts the variation in the standard deviation of thedifference between the simulated temperature and the reference profileas a function of the error on the diffusion and absorption parameters ofthe treated tissues, which error is calculated as the ratio$\frac{\left( {D/\alpha} \right)\quad {erroneous}}{\left( {D/\alpha} \right)\quad {optimum}}.$

[0071] These results reveal a significant correlation between the errorin D/α and the precision of the control algorithm. In addition, it canbe seen that an error in estimating α and D (due in particular to theirvariation during the course of the experiment) has little effect on thequality of the control. These results confirm the effectiveness androbustness of the proposed method.

[0072] The real time temperature control of local hyperthermia can beperformed in vivo on a clinical MRI. This simple and predictive methodbased on the physical model of the temperature diffusion depends only onthe absorption (α) and diffusion (D) coefficients of the tissues. Themathematical expression of the proposed algorithm is very general andcan therefore be applied to any energy source (focused ultrasound,radiofrequency, laser, microwaves, etc.) that allows hyperthermia to beinduced in biological tissues. The only condition governing its use isknowledge of the spatial profile of the application of energy.

1. An assembly for the heat treatment of a region of biological tissue(410) comprising: energy-generating means (100) to supply energy to theregion, means (200) for measuring and recording the spatial temperaturedistribution in said region, control unit (300) comprising numericalprocessing means for the point-by-point processing of the spatialtemperature distribution in the region, characterized in that theenergy-generating means comprise means (110) for spatially andtemporally distributing the power that they apply to the aforesaidregion, the control unit (300) comprising means (330, 350) for, on thebasis of the temperature distribution, controlling the amount anddistribution of the energy supplied by the generating means (100). 2.The heat treatment assembly as claimed in claim 1, characterized in thatthe control unit (300) further comprises means (340) for estimating theenergy losses in the region of the tissue (410) on the basis of anestimate of the thermal conductivity and of the spatial temperaturedistribution in the region and its surroundings.
 3. The heat treatmentassembly as claimed in one of the preceding claims, characterized inthat the control unit (300) comprises processing means (330, 350) totake account of the thermal conductivity at each point in the region. 4.The heat treatment assembly as claimed in claim 3, characterized in thatthe control unit (300) comprises means (320) for measuring thetemperature at each point of a plurality of points sampling the regionand at regular time intervals and to deduce therefrom an estimate of thechange in temperature as a function of thermal conductivity from onepoint of the spatial sample to another.
 5. The heat treatment assemblyas claimed in one of the preceding claims, characterized in that theenergy-generating means (100) emit focused ultrasound.
 6. The heattreatment assembly as claimed in one of the preceding claims,characterized in that the means (200) for measuring and recording thespatial temperature distribution comprise a magnetic resonance imagingapparatus.
 7. The heat treatment assembly as claimed in one of thepreceding claims, characterized in that the amplitude pw of the power tobe supplied at a point {right arrow over (r)} at an instant t+Δt iscalculated using a relationship of the type:${pw} = \frac{{{Tp}\left( {\overset{\rightarrow}{r},{t + {\Delta \quad t}}} \right)} - {{FT}^{- 1}\left( {T*\left( {\overset{\rightarrow}{k},t} \right)^{{- k^{2}}D\quad \Delta \quad t}} \right)}}{{FT}^{- 1}\left( {\alpha \frac{1 - ^{{- k^{2}}D\quad \Delta \quad t}}{{Dk}^{2}}S*\left( \overset{\rightarrow}{k} \right)} \right)}$

where Tp({right arrow over (r)},t+Δt) is the reference temperature atthat point at the moment t+Δt, FT⁻¹ is an inverse Fourier transform,T*({right arrow over (k)},t) is the Fourier transform of the temperaturemeasured at the moment t, D is the heat diffusion coefficient for thetissue, α is the energy absorption coefficient for the tissue, S*({rightarrow over (k)}) is the Fourier transform of the spatial distribution ofthe applied energy S({right arrow over (r)}).
 8. Heat treatment assemblyaccording to one of the preceding claims, characterized in that theenergy-generating means (100) comprise energy sources of the ultrasound,laser, microwave or radiofrequency type.